The present invention relates to 2-adamantylethylamines and their use in the treatment of conditions generally associated with abnormalities in glutamatergic transmission.
The excitatory neurotransmission underlying brain function is primarily (about 80 percent) dependent on the action of glutamate and other related neurotransmitters on specific receptors activated by the excitatory amino acids. These receptors fall into several categories, one of which is the glutamate receptor specifically sensitive to the agonist N-methyl-D-aspartate (the NMDA receptor). NMDA receptor subtypes are ubiquitously expressed in mammalian brain and have unique properties underlying their role in synaptic function and plasticity. In view of the central role of these receptors in normal central nervous system function, numerous suggestions have been made as to the utility of drugs acting at this receptor to modulate the processes underlying various disease states. The NMDA receptor has been studied with particular interest in relation to its apparent involvement in the pathophysiology of neurodegenerative diseases and states of neuropathic pain.
Non-competitive antagonists at this receptor should be particularly advantageous in the treatment of diseases since such compounds would have activity that should not be overcome by high levels of endogenous agonists and would act equally well independent of the endogenous agonist activating the receptor. This is important since high levels of endogenous glutamate can occur in certain pathological processes and there are a variety of different endogenous agonists that can act through a variety of specific modulatory agonist binding sites on the receptor.
A number of NMDA antagonists have been disclosed which operate by binding to the ion-channel of the NMDA receptor. The advantage of channel blockers is that they operate only on the xe2x80x9copenxe2x80x9d channel and therefore do not affect unactivated receptors. In addition they are effective regardless of the mechanism of receptor stimulation and their effect will not be diminished by large concentrations of endogenous agonist.
Given that the NMDA receptor plays a primary role in normal central nervous system function, it is not surprising that certain drugs acting to block or antagonise the function of this receptor affect normal function within the brain. This may be manifested as central nervous system side effects such as hallucinations, confusion, paranoia, aggression, agitation and catatonia. These side effects can be described as a psychotic state and the drugs that induce them are known as psychotomimetic NMDA antagonists. Such side effects limit the utility of these compounds in treating disease states. NMDA receptor antagonists that have efficacy in treating central nervous system disorders but without such psychotomimetic side effects would have a clear therapeutic advantage. Thus, in view of the crucial role played by the NMDA receptor in either the progression or expression of the disease pathology and process, it is an object of this invention to provide compounds for the treatment of central nervous system disorders which modulate the activity of the NMDA receptor but which are well-tolerated in the sense of having a markedly reduced propensity to induce psychotomimetic side effects.
The present invention is particularly concerned with the treatment of neurodegenerative disorders and the treatment of pain. There is a large body of evidence to suggest that either an excitotoxic or slow excitotoxic pathological over-activation of the NMDA receptor induces the death of neurons in a variety of disorders such as ischaemic stroke, other forms of hypoxic injury, haemorrhagic brain injury, traumatic brain injury, Alzheimer""s disease, Parkinson""s disease, Huntington""s disease and other dementing diseases. There is thus clear evidence that antagonism of the NMDA receptor will reduce or prevent the neurodegeneration that underlies the disease process in these and related conditions. There is also evidence to suggest that a well-tolerated compound will allow effective symptomatic treatment of the manifestations of the disease process in these disorders as well as reducing the primary underlying neurodegeneration process. Also, it is known that some disorders previously described as involving acute neurodegeneration have longer than expected elevations in extracellular concentrations of glutamate and consequently require longer than expected treatment with NMDA antagonists. There would therefore be a therapeutic advantage for new drugs which are well-tolerated and which can therefore be administered chronically.
Similarly, there is a substantial body of evidence available in the literature, regarding both pre-clinical and clinical studies, suggesting NMDA receptor involvement in the perception of pain, the generation of persistent neuropathic pain states, and the development of tolerance to traditional analgesics. It has been long known that NMDA receptor antagonists prevent behaviours mediated by nociceptive stimuli in experimental animals, as would be expected of analgesics. Similarly, experimental studies on C-fibre responses, for example, have shown the role of NMDA receptor antagonists in blocking long lasting activity thought to reflect neuropathic pain. Neuropathic pain is not well treated by traditional analgesics, such as opiates or non-steroidal anti-inflammatory agents. Neuropathic pain occurs during diabetic neuropathy, AIDS-related neuropathy, postherpetic neuralgia, chronic degenerative spinal disease, sympathetic dystrophies, post-amputation stump pain (phantom limb), trigeminal neuralgia, thalamic pain syndrome, sciatica and multiple sclerosis.
Whilst pain due to cancer can be treated with opiate analgesics, the effect of opiates in producing pain relief in cancer diminishes with time. This phenomenon is known as opiate tolerance. Both pre-clinical and clinical studies have shown that NMDA antagonists prevent the development of opiate tolerance and have an xe2x80x9copiate sparingxe2x80x9d effect. This means that administration of an NMDA antagonist alongside an opiate may result in the treatment of cancer pain using less opiate and with a more persistent effect.
The published literature contains references to a number of compounds and classes of compounds purported to be useful as NMDA antagonists.
The compounds Amantadine and Memantine and related anti-viral agents have been known for many years. 
Patent applications have been filed directed to the use of Memantine in the treatment of Parkinson""s Disease in the 1970s and as an NMDA antagonist in 1990 (see EP-A-0392059 and U.S. Pat. No. 5,061,703). Furthermore, International Patent application WO94/05275 proposes the use of Amantadine and related compounds such as Memantine in the treatment and prevention of non-ischaeric, long term NMDA receptor-mediated neuronal degeneration. An increase in affinity for the NMDA receptor due to substitution of the adamantane ring of Amantadine with alkyl groups was noted and published in Kornhuber et al. (Eur. J. Pharmacol., 1991, 206, 297-300). Structure-activity relationships relating to 1-(adamantyl)alkanamines are reported by Kroemer et al. (J. Med. Chem.,1998, 41, 393-400), by Parsons et al. (Neuropharmacology, 1995, 34, 1239-1258) and by Fytas et al. (II Farmaco,1994, 49, 641-647).
As discussed above, psychotomimetic side-effects are observed during the use of a number of well known NMDA receptor channel blockers and therefore it will be a considerable advantage to identify clinically well-tolerated antagonists where such side effects are minimised.
The use of a number of the known NMDA antagonists such as Dizocilpine (MK-801), phencyclidine (PCP), Cerestat and Ketamine gives rise to a number of side effects which render these compounds unsuitable for use in treatment. In particular, administration of the compounds is associated with perceptual and cognitive disturbances of a kind that resemble naturally-occurring psychotic states.
In addition, the perceptual and cognitive side effects of the compounds become more pronounced after the onset of puberty and sexual maturation, and these compounds are therefore particularly unsuitable for the treatment of adults. This developmental change has been demonstrated empirically in both experimental animals and in man, and is paralleled in experimental animals by brain hypermetabolism.
As noted above, non-competitive NMDA receptor channel blockers are frequently associated with the causation of psychotic states in clinical use. The prototypical compound phencyclidine (PCP), when administered to man, usually achieves tissue levels similar to the potency of this compound in its action as an NMDA receptor channel blocker. Such tissue levels are associated with an acute psychotic state clinically indistinguishable from an acute schizophreniform breakdown. In experimental animals administration of doses that produce equivalent tissue levels induces a characteristic behavioural state. This behavioural state comprises of the production of head weaving, circling, reciprocal fore paw treading and hyperactivity, as is known as the xe2x80x9cPCP syndromexe2x80x9d. The induction of the xe2x80x9cPCP syndromexe2x80x9d is unique and specific to NMDA receptor channel blocking agents that are psychotomimetic in man. Competitive antagonists acting at agonist binding sites on the NMDA receptor do not elicit this xe2x80x9cPCP syndromexe2x80x9d and are not psychotomimetic in man. Our data show that memantine, an NMDA receptor channel blocking agent, also elicits xe2x80x9cPCP syndromexe2x80x9d, as shown in FIG. 1.
We have also shown that ketamine, an NMDA receptor channel blocking agent with a similar binding potency to memantine, also produces xe2x80x9cPCP syndromexe2x80x9d confirming that this syndrome reflects activity in a compound known to be psychotomimetic in man (see FIG. 3).
In summary, there is a need for an NMDA antagonist which is well-tolerated and does not give rise to the side effects associated with previous clinically investigated NMDA antagonists.